Beyond U0126. Dianion chemistry leading to the rapid synthesis of a series of potent MEK inhibitors

被引：24

作者：

Wityak, J ^{[1
]}

Hobbs, FW ^{[1
]}

Gardner, DS ^{[1
]}

Santella, JB ^{[1
]}

Petraitis, JJ ^{[1
]}

Sun, JH ^{[1
]}

Favata, MF ^{[1
]}

Daulerio, AJ ^{[1
]}

Horiuchi, KY ^{[1
]}

Copeland, RA ^{[1
]}

Scherle, PA ^{[1
]}

Jaffe, BD ^{[1
]}

Trzaskos, JM ^{[1
]}

Magolda, RL ^{[1
]}

Trainor, GL ^{[1
]}

Duncia, JV ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 06期

关键词：

D O I：

10.1016/j.bmcl.2004.01.012

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Employing phenylmalonitrile dianion chemistry, a large number of analogues of MEK inhibitor lead SH053 (IC50 = 140 nM) were rapidly synthesized leading to single digit nM inhibitors, displaying submicromolar AP-1 transcription inhibition in COS-7 cells. Compound 41, exhibiting a MEK IC50 = 12 nM showed ip activity in a TPA-induced car edema model with an ED50 = 5 mg/kg. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：1483 / 1486

页数：4

共 15 条

[1]

AVERY MA, 1997, BURGERS MED CHEM DRU, P286

[2] Synthesis and evaluation of 4-anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade [J].

Berger, D ;

Dutia, M ;

Powell, D ;

Wu, BQ ;

Wissner, A ;

Boschelli, DH ;

Floyd, MB ;

Zhang, N ;

Torres, N ;

Levin, J ;

Du, XM ;

Wojciechowicz, D ;

Discafani, C ;

Kohler, C ;

Kim, SC ;

Feldberg, LR ;

Collins, K ;

Mallon, R .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (18) :3031-3034

[3] Molecular mechanisms of anti-inflammatory action of glucocorticoids [J].

Cato, ACB ;

Wade, E .

BIOESSAYS, 1996, 18 (05) :371-378

[4]

COPELAND RA, 1996, ENZYMES PRACTICAL IN, P187

[5] A NEW SYNTHESIS OF ARYLMALONONITRILES [J].

DAVIS, WA ;

CAVA, MP .

JOURNAL OF ORGANIC CHEMISTRY, 1983, 48 (16) :2774-2775

[6] A SYNTHETIC INHIBITOR OF THE MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE [J].

DUDLEY, DT ;

PANG, L ;

DECKER, SJ ;

BRIDGES, AJ ;

SALTIEL, AR .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (17) :7686-7689

[7] MEK inhibitors: The chemistry and biological activity of U0126, its analogs, and cyclization products [J].

Duncia, JV ;

Santella, JB ;

Higley, CA ;

Pitts, WJ ;

Wityak, J ;

Frietze, WE ;

Rankin, FW ;

Sun, JH ;

Earl, RA ;

Tabaka, AC ;

Teleha, CA ;

Blom, KF ;

Favata, MF ;

Manos, EJ ;

Daulerio, AJ ;

Stradley, DA ;

Horiuchi, K ;

Copeland, RA ;

Scherle, PA ;

Trzaskos, JM ;

Magolda, RL ;

Trainor, GL ;

Wexler, RR ;

Hobbs, FW ;

Olson, RE .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1998, 8 (20) :2839-2844

[8] Identification of a novel inhibitor of mitogen-activated protein kinase kinase [J].

Favata, MF ;

Horiuchi, KY ;

Manos, EJ ;

Daulerio, AJ ;

Stradley, DA ;

Feeser, WS ;

Van Dyk, DE ;

Pitts, WJ ;

Earl, RA ;

Hobbs, F ;

Copeland, RA ;

Magolda, RL ;

Scherle, PA ;

Trzaskos, JM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (29) :18623-18632

[9] THE STEROID-RECEPTOR SUPERFAMILY - MECHANISMS OF DIVERSITY [J].

FULLER, PJ .

FASEB JOURNAL, 1991, 5 (15) :3092-3099

[10] STEROID-HORMONE RECEPTORS - BIOCHEMISTRY, GENETICS, AND MOLECULAR-BIOLOGY [J].

GEHRING, U .

TRENDS IN BIOCHEMICAL SCIENCES, 1987, 12 (10) :399-402

← 1 2 →